Apoptosis is the major independent form of cardiomyocyte cell death in acute myocardial infarction (AMI). TNF-alpha release early in the course of AMI contributes to myocardial injury and TNF-alpha induces apoptosis in cardiomyocytes. Soluble TNF-alpha receptor 1 (sTNFR1) is an extracellular domain of TNER1 and an antagonist to TNF-alpha. Treatment with sTNFR1plasmid reduced the TNF-alpha bioactivity in the myocardium and the apoptosis of cardiomyocytes. As a result, the sTNFR1 plasmid significantly reduced the area of myocardial infarction at 2 days after coronary artery ligation. In a pathological setting, TNF-alpha inhibits the proliferative response of endothelial cells through inactivation of receptors for vascular endothelial growth factor (VEGF). Growth of HUVEC trarisfected with sTNFRI vector increased significantly compared to those transfected with control vector. The TNF-alpha-induced internucleosomic fragmentation was also significantly prevented in HUVEC transfected with sTNFRI vector compared to those trarisfected with control vector. In a rat model of hindlimb ischemia, VEGF increased but activation of KDR/flk-1 was suppressed possibly by TNF-alpha, which might impair angiogenesis. Suppression of TNF-alpha with sTNFR1 plasmid upregulated KDR/flk-1 and accelerated angiogenesis.